Download Chapter 16 - Lipid Metabolism

Chapter 16 - Lipid Metabolism
• Triacylglycerols (TGs) and glycogen are the
two major forms of stored energy in vertebrates
• Glycogen can supply ATP for muscle contraction
for less than an hour
• Sustained work is fueled by metabolism of TGs
which are very efficient energy stores because:
(1) They are stored in an anhydrous form
(2) Their fatty acids are more reduced than
amino acids or monosaccharides
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16.1 Adsorption and Mobilization of Fatty Acids
• Fatty acids (FA) and glycerol for metabolic
fuels are obtained from triacylglycerols:
(1) In the diet
(2) Stored in adipocytes (fat storage cells)
• Free fatty acids occur only in trace amounts in
cells
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A. Absorption of Dietary Lipids
• Most diet lipids of mammals are TGs
• In the small intestine, fat particles are coated
with bile salts and digested by pancreatic lipases
• Lipases degrade TGs to free fatty acids and a
2-monoacylglycerol
• Lipase catalyzes hydrolysis at the C-1 and C-3
positions of a TG
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Fig 16.1 Bile salts
• Taurocholate and glycocholate (cholesterol
derivatives) are the most abundant bile salts
• Amphipathic: hydrophilic (blue), hydrophobic (black)
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Fig 16.2 Action of pancreatic lipase
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Fig 16.3 Dietary phospholipids are
degraded by phospholipases
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Fig 16.4 Structure of phospholipase A2
from cobra venom
• Phospholipid substrate in
the active site
• Calcium ion (purple)
binds anionic head group
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Dietary cholesterol
• Most dietary cholesterol is unesterified
• Cholesteryl esters are hydrolyzed by an
intestinal esterase
• Free cholesterol is solublized by bile-salt
micelles for adsorption
• Cholesteryl acyl CoA esters are formed in the
intestinal cells
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B. Lipoproteins
• TGs, cholesterol and cholesterol esters are
insoluble in water and cannot be transported in
blood or lymph as free molecules
• These lipids assemble with phospholipids and
apoproteins (apolipoproteins) to form spherical
particles called lipoproteins with:
Hydrophobic cores: TGs, cholesteryl esters
Hydrophilic surfaces: cholesterol, phospholipids,
apolipoproteins
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Fig 16.5 Structure of a lipoprotein
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Chylomicrons
• Chylomicrons are the largest lipoproteins
• They deliver TGs from the intestine (via lymph
and blood) to tissues (muscle for energy,
adipose for storage)
• They are present in blood only after feeding
• Cholesterol-rich chylomicron remnants deliver
cholesterol to the liver
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Fig 16.6 Summary of lipoprotein metabolism
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Table 16.1
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C. Storage and Mobilization
of Fatty Acids (FA)
• TGs are stored in adipocytes, and fatty acids are
released to supply energy demands
• A hormone-sensitive lipase converts TGs to free
fatty acids and glycerol
• At low carbohydrate and insulin concentrations,
TG hydrolysis is stimulated by increased
epinephrine (binds to b-adrenergic receptors,
and activates cAMP-dependent protein kinases)
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Fig 16.7 Triacylglycerol degradation
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16.2 Fatty Acid Oxidation
• The β-oxidation pathway degrades fatty acids
two carbons at a time
• Three stages:
(1) Activation of fatty acids in the cytosol
(2) Transport into the mitochondria
(3) Degradation to two-carbon fragments
(as acetyl CoA) in the mitochondrial matrix
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A. Activation of Fatty Acids
• Fatty acids in the cytosol are activated by
conversion to CoA thioesters by acyl-CoA
synthetase (ATP dependent)
• The PPi released is hydrolyzed by a
pyrophosphatase to 2 Pi
• Net of two ATP equivalents are consumed to
activate one fatty acid to a thioester
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Activation of fatty acids: reaction
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B. Transport of Fatty Acyl CoA into Mitochondria
• The carnitine shuttle system transfers longchain fatty acyl CoA from the cytosol into the
mitochondria
• Fatty acyl CoA is first converted to acylcarnitine
(which can enter the mitochondria) and then
back to fatty acyl CoA
• The β-oxidation cycle enzymes (mitochondrial)
can then degrade the fatty acyl CoA
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Fig 16.8
• Carnitine
shuttle
system
• Path of acyl
group in red
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C. The Reactions of β oxidation
• One round of β oxidation: 4 enzyme steps
produce acetyl CoA from fatty acyl CoA
• Each round generates one molecule each of:
QH2
NADH
Acetyl CoA
Fatty acyl CoA (2 carbons shorter each round)
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Fatty acyl CoA
Fig 16.9
β-Oxidation
of saturated
fatty acids
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Fig 16.9 (continued)
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D. ATP Generation from Fatty Acid Oxidation
• The balanced equation for oxidizing one
palmitoyl CoA by seven cycles of β oxidation
Palmitoyl CoA + 7 HS-CoA + 7 Q + 7 NAD+ + 7 H2O
8 Acetyl CoA + 7QH2 + 7 NADH + 7 H+
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Net yield of ATP per palmitate oxidized to 16 CO2
ATP generated
8 acetyl CoA
7 QH2
7 NADH
80
10.5
17.5
108 ATP
ATP expended to activate palmitate -2
Net yield:
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106 ATP
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16.3 β Oxidation of Odd-Chain and
Unsaturated Fatty Acids
• Odd-chain fatty acids occur in bacteria and
microorganisms
• Final cleavage product is propionyl CoA rather
than acetyl CoA
• Three enzymes convert propionyl CoA to
succinyl CoA (citric acid cycle intermediate)
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Fig 16.10
Conversion of
propionyl CoA to
succinyl CoA
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Fig 16.10 (cont)
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β Oxidation of Unsaturated Fatty Acids
• Unsaturated FA are common in nature
• Degradation requires two other enzymes in
addition to the β-oxidation pathway enzymes:
(1) Enoyl-CoA isomerase
(2) 2,4-Dienoyl-CoA-reductase
(Fig 16.11 - Pathway is on the next two slides)
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16.4 Ketone Bodies Are Fuel Molecules
• During fasting or starvation, glucose is decreased,
and excess acetyl CoA from fat metabolism can
be converted to ketone bodies:
β-Hydroxybutyrate
Acetoacetate
Acetone
• Ketone bodies can fuel brain cells during
starvation
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Fig 16.12 Ketone bodies
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A. Ketone Bodies Are Synthesized in the Liver
Fig 16.13
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Fig 16.13
(cont)
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B. Ketone Bodies Are Oxidized in Mitochondria
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16.5 Fatty Acid Synthesis
• Occurs mainly in liver and adipocytes (mammals)
• FA synthesis and degradation occur by two
completely separate pathways
• When glucose is plentiful, large amounts of acetyl
CoA are produced by glycolysis and can be used
for fatty acid synthesis
• Glucose oxidation in the pentose phosphate
pathway provides NADPH for FA synthesis
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Table 16.2
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A. Transport of Acetyl CoA to the Cytosol
• Acetyl CoA from catabolism of carbohydrates
and amino acids is exported from mitochondria
via the citrate transport system (Fig 16.15,
next slide)
• Cytosolic NADH also converted to NADPH
• Two molecules of ATP are expended for each
round of this cyclic pathway
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Fig. 16.15 Citrate transport system
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B. Carboxylation of Acetyl CoA
Fig 16.16 Acetyl CoA carboxylase catalyzes:
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C. The Reactions of Fatty Acid Synthesis
• FA are synthesized by the repetitive condensation
of two-carbon units derived from malonyl CoA
• Five separate stages:
(1) Loading of precursors via thioester derivatives
(2) Condensation of the precursors
(3) Reduction
(4) Dehydration
(5) Reduction
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Fig 16.17 Biosynthesis of FA from acetyl
CoA and malonyl CoA in E. coli
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Fig 16.17 (continued)
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Fig. 16.17 (continued)
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Fig 16.18
Condensation step
for second round of
FA biosynthesis
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Final reaction of FA synthesis
• Rounds of synthesis continue until a
C16 palmitoyl group is formed
• Palmitoyl-ACP is hydrolyzed by a thiolesterase
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Overall stoichiometry of palmitate synthesis
from acetyl CoA and malonyl CoA
Acetyl CoA + 7 Malonyl CoA + 14 NADPH + 14 H+
Palmitate + 7 CO2 + 14 NADP+ + 8 HS-CoA + 6 H2O
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Fig 16.19
• Organization of
subunits in animal
FA synthase
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Fig 16.20 Early steps in reactions
of animal FA synthase (2 slides)
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Fig 16.20 (continued)
(from previous slide)
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16.6 Fatty Acid Elongation and Desaturation
Fig 16.21
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Fig 16.21 (cont)
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16.7 Regulation of Fatty Acid Oxidation
• FA synthesis and oxidation are reciprocally
regulated
• Fed state: Storage is favored (carbohydrates are
used as fuel a precursors for FA synthesis)
• Fasting state: FA oxidation is favored as fats
serve as fuel in place of glucose
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Control points for FA oxidation
Fed state: Insulin (levels increase)
• Inhibits hydrolysis of stored TGs
• Stimulates formation of malonyl CoA, which
inhibits CAT I
• FA remain in cytosol (FA oxidation enzymes are
in the mitochondria)
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Control points for FA oxidation (cont)
Fasted state: Epinephrine and glucagon
increase (insulin decreases)
• Epinephrine activates lipase enzyme to produce
more FA
• Glucagon inactivates malonyl CoA synthesis
enzyme (leads to increased transport of FA into
mitochondria and the β-oxidation pathway)
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FA synthesis regulation via
acetyl CoA carboxylase
• Acetyl CoA carboxylase is inhibited by fatty
acyl CoA (increased FA concentrations lead to
decreased FA synthesis)
• Acetyl CoA carboxylase is under hormonal
control: glucagon and epinephrine (fasted
state) stimulate phosphorylation (inactivation)
of the enzyme
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16.8 Synthesis of Eicosanoids
• Arachidonate is the precursor of eicosanoids
(regulatory molecules) (Fig 16.22, next 2 slides)
• Eicosanoids
(1) Prostaglandins and thromboxanes are
local regulators (act at site of synthesis) and
include: prostacyclin, thromboxane A2
(2) Leukotrienes
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16.9 Synthesis of Triacylglycerols (TGs)
and Glycerophospholipids (GPLs)
• Most fatty acids in cells are found in esterified
forms as TGs or GPLs
• Phosphatidic acid (phosphatidate) is an
intermediate in the synthesis of TGs and GPLs
• Glycerol 3-phosphate is acylated by fatty acyl
CoA molecules
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Fig 16.23 Formation of phosphatidate
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Fig 16.24 Synthesis of TGs and
neutral phospholipids
(Continued next
2 slides)
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Fig16.25 Synthesis of acidic phospholipids
(Continued next slide)
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Fig 16.25 (continued)
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Fig 16.26
• Interconversions of
phosphatidylethanolamine (PE),
phosphatidylserine
(PS)
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16.10 Synthesis of Ether Lipids
• These lipids have an ether linkage in place of
one ester linkage of phospholipids
• Dihydroxyacetone is the starting point for
synthesis of the ether lipids
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Fig 16.27 Synthesis of ether lipids
(continued next slide)
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(from previous slide)
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Fig 16.27
(cont)
(from previous slide)
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16. 11 Synthesis of Sphingolipids
• Sphingolipids are membrane lipids that have
sphingosine (a C18 unsaturated alcohol) as the
structural backbone
• Sphingolipids include sphingomyelins and
cerebrosides
• Condensation of serine and palmitoyl CoA
produces 3-ketosphinganine to start the pathway
(Figure 16.28, next two slides)
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(continued from
previous slide)
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16.12 Synthesis of Cholesterol
• Cholesterol is a precursor of steroid hormones
and bile acids, and an important component of
many mammalian membranes
• Most cholesterol is synthesized in the liver
• Liver-derived and dietary cholesterol are both
delivered to body cells by lipoproteins
• Cholesterol biosynthesis is regulated by
hormones and blood cholesterol levels
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Summary: stages of cholesterol
biosynthesis
Acetate (C2)
Isoprenoid (C5)
Squalene (C30)
Cholesterol (C27)
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A. Stage 1: Acetyl CoA to
Isopentenyl Pyrophosphate
• The carbons of cholesterol come from cytosolic
acetyl CoA (transported from mitochondria via
citrate transport system)
• First step is a sequential condensation of three
molecules of acetyl CoA
• Isopentenyl pyrophosphate is an important
donor of isoprenyl groups for many synthetic
reactions
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Fig 16.29
• Stage I of
Cholesterol
Biosynthesis
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Fig 16.29
(continued)
(continued from
previous slide)
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HMG-CoA reductase
• Catalyzes first committed step in pathway
• Primary site for regulating cholesterol synthesis
• Three regulatory mechanisms:
Covalent modification
Repression of transcription
Control of degradation
• Cholesterol-lowering statin drugs (e.g.
Lovastatin) inhibit HMG-CoA reductase
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Fig 16.30 Lovastatin resembles mevalonate
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B. Stage 2
• Fig 16.31
Isopentenyl
Pyrophosphate
to Squalene
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Fig 16.31
(cont)
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C. Stage 3:
• Squalene to
Cholesterol
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D. Other Products of Cholesterol Metabolism
• Many isoprenoids are synthesized from
cholesterol or its precursors
• Isopentenyl pyrophosphate (C5) is a precursor
of a large number of products
• Figure 16.33 (next slide) summarizes the
products of cholesterol metabolism
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16.13 Lipids Are Made at a
Variety of Sites
• Most lipid biosynthesis in eukaryotic cells occurs
in the endoplasmic reticulum (PC, PE, PI, PS)
• Enzymes of lipid synthesis are membranebound with active sites facing the cytosol
• Other lipid synthesis locations include: plasma
membrane, mitochondria, lysosomes and
peroxisomes
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